Recent data indicate substantial health disparities in lesbian, gay, and bisexual (LGB) populations, including nearly twice the risk of substance use among LGB youths compared to their heterosexual peers. Additionally, young gay/bisexual men, already disproportionately burdened with HIV morbidity, are one of the only risk groups in which new HIV infection rates are increasing. A 2011 report on LGB health released by the Institute of Medicine (IOM) noted the dearth of research on the factors responsible for these disparities. This report identified the study of social ecological influences as a priority researc area, and emphasized the need for studies that adopt minority stress and life course perspectives in order to determine how the unique issues confronting LGB populations increase their risk for adverse health outcomes. This Mentored Research Scientist Development Award (K01) will provide the candidate with the protected time, training, and resources necessary to carry out these research priorities established in the IOM report. The goal of the Award is to develop an interdisciplinary research program focused on identifying modifiable social ecological factors that can explain and address health disparities among LGB youth. To accomplish his career goals and research objectives, the candidate requires training and mentorship in social epidemiology, biostatistical approaches to life course studies, and stress biology. This training will be accomplished through a combination of mentored research projects, courses, seminars, and conferences. The new skills that are acquired will enable the candidate to conduct innovative, high-impact research examining how and why the social environment surrounding LGB youth contributes to their increased risk for substance use and associated problems. The over-arching objectives of this research are: (1) to evaluate whether sexual minority stress measured at the social ecological level predicts substance use and HIV risk behaviors within LGB youth and explains sexual orientation-related disparities in these outcomes; (2) to identify modifiable contextual factors that protect LGB youth from engaging in substance use and HIV risk behaviors; and (3) to elucidate biological pathways that mediate the relationship between sexual minority stress, substance use, and HIV risk behaviors. This proposal uses a multi-method framework that draws on the strengths of two prospective cohort studies (the Growing Up Today Study and the National Longitudinal Study of Adolescent Health) that have followed LGB and heterosexual adolescents for over 15 years. These epidemiologic studies will be complemented by data collection in two studies that utilize experimental and experience-sampling designs. This research will address novel questions about social determinants of LGB health, their interplay with individual biological factors, and how these processes emerge over the life course. Moreover, the results will facilitate the development of structural, policy, and community-level interventions that reduce sexual orientation-related disparities in substance use and HIV risk behaviors, an important priority at NIDA.